Parkinson's disease (PD) is one of the most common neuro-degenerative diseases characterized by alpha-synuclein accumulation and degeneration of dopaminergic neurons. Employing genome-wide sequencing, we identified a polymorphic USP8 allele (USP8D442G) significantly enriched in Chinese PD patients. To test the involvement of this polymorphism in PD pathogenesis, we derived dopaminergic neurons (DAn) from human-induced pluripotent stem cells (hiPSCs) reprogrammed from fibroblasts of PD patients harboring USP8D442G allele and their healthy siblings. In addition, we knock-in D442G polymorphic site into the endogenous USP8 gene of human embryonic stem cells (hESCs) and derived DAn from these knock-in hESCs to explore their cellular phenotypes and molecular mechanism. We found that expression of USP8D442G in DAn induces the accumulation and abnormal subcellular localization of alpha-Synuclein (alpha-Syn). Mechanistically, we demonstrate that D442G polymorphism enhances the interaction between alpha-Syn and USP8 and thus increases the K63-specific deubiquitination and stability of alpha-Syn . We discover a pathogenic polymorphism for PD that represent a promising therapeutic and diagnostic target for PD.
基金：
This work was supported by the National Natural Science
Foundation of China (Nos. 81930084, U1601222), National Key
Research and Development Program of China (2022YFC3401600),
the Fundamental Research Funds for the Central Universities (No.
2021FZZX001-42), Ministry of Science and Technology of China
(2103ZX10002008002), the Key Research and Development Program
of Guangdong Province (2019B020235003), Department of Science
and Technology of Guangdong Province (2020A1515110450), Traditional
Chinese Medicine Bureau Of Guangdong Province of China
(20211183, 20225009), the Special Project of State Key Laboratory
of Dampness Syndrome of Chinese Medicine (SZ2021KF15) and the
Specific Research Fund for TCM Science and Technology of Guangdong
Provincial Hospital of Chinese Medicine (YN2015QN04 and
2020KT1079).
第一作者机构：[1]Guangzhou Univ Chinese Med, State Key Lab Dampness Syndrome Chinese Med, Affiliated Hosp 2, Guangzhou, Peoples R China[2]Guangzhou Univ Chinese Med, Chinese Med Sci, Ctr Regenerat & Translat Med, Affiliated Hosp 2,Guangdong Prov Acad, Guangzhou, Peoples R China
通讯作者：
推荐引用方式(GB/T 7714)：
Wu Shouhai,Lin Tongxiang,Xu Yang.Polymorphic USP8 allele promotes Parkinson's disease by inducing the accumulation of α-synuclein through deubiquitination[J].CELLULAR AND MOLECULAR LIFE SCIENCES.2023,80(12):doi:10.1007/s00018-023-05006-0.
APA：
Wu, Shouhai,Lin, Tongxiang&Xu, Yang.(2023).Polymorphic USP8 allele promotes Parkinson's disease by inducing the accumulation of α-synuclein through deubiquitination.CELLULAR AND MOLECULAR LIFE SCIENCES,80,(12)
MLA：
Wu, Shouhai,et al."Polymorphic USP8 allele promotes Parkinson's disease by inducing the accumulation of α-synuclein through deubiquitination".CELLULAR AND MOLECULAR LIFE SCIENCES 80..12(2023)
生物学